ABSTRACT *This proposal describes an innovative biomaterials solution to the problem of local recurrence following surgery for non-small cell lung cancer. Despite surgery, approximately 22% of early-stage patients develop locoregional recurrence attributed to remaining occult local residual disease. This problem results from attempts to minimize the loss of pulmonary function by removing as little lung tissue as possible and from microscopic tumor cells remaining near the surgical resection margin. Our solution is a buttress, which is stapled into the resection margin during the procedure, to: 1) deliver prolonged high local concentrations of anti-cancer agents in a controlled manner to the tissue harboring the residual cancer (and regional lymph nodes); and 2) seal the tissue to prevent air leaks upon stapling. This novel biomaterials/surgical approach changes the paradigm by allowing the surgeon to remove less lung tissue while treating any potential residual tumor burden effectively. We describe unique electrospun polymeric non-woven meshes whereby the polymer composition and the bulk superhydrophobic property (i.e., resist wetting and have high apparent contact angles) control drug release. The proposed experiments will test the hypothesis that local delivery of established (paclitaxel & cisplatin) and new (eupenifelden) agents via a 3-D superhydrophobic buttress, possessing controlled wettability, will afford sustained release and cytotoxicity for greater than 60 days. We further hypothesize that a dual drug- loaded (e.g., paclitaxel & cisplatin) buttress will reduce locoregional recurrence rates and extend survival in a patient-derived lung cancer xenograft (PDX) surgical model, and prove to be safe and feasible for locoregional drug delivery without adverse systemic effects or impaired local healing. Importantly, substantial preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address the hypotheses. The specific aims of this five-year proposal are: Aim 1. Characterize the wetting rates and the release kinetics of single and combined hydrophobic (paclitaxel or eupenifelden) and hydrophilic (cisplatin) agents from superhydrophobic buttresses as well as the sealing capability on ex vivo lung tissue; Aim 2. Investigate efficacy and pharmacodynamic profiling of single and dual drug-loaded superhydrophobic buttress response against resected patient-derived lung tumors in vitro; and, Aim 3. Evaluate the efficacy of drug-loaded superhydrophobic buttresses in preventing lung cancer recurrence following resection in a patient-derived xenograft (PDX) murine model as well as assess the safety, local tissue healing, and drug pharmacokinetics/biodistribution after buttress implantation.